Canagliflozin in diabetic kidney disease

Overview

Perkovic V et al.. N Engl J Med 2019 · PMID 30990260 · DOI 10.1056/NEJMoa1811744

Kidney failure and heart problems fell by about a third; amputations and fractures were not increased, but rare ketoacidosis was more common (11 vs 1 cases).

Does the study support the specific claim? No · Methodological quality: high

Original publication

Plain-language summary

Scientific in-depth review

1. Full reference

Authors

Perkovic V et al.

Journal

N Engl J Med

Year

2019

Identifier

PMID 30990260 DOI 10.1056/NEJMoa1811744

Verification

verified – PubMed efetch 2026-10-25 (this agent)

Retracted

no

Corrections

none

Extent checked

full text

Conflicts of interest and funding

Sponsored by Janssen Research and Development (manufacturer) in collaboration with an academic steering committee and George Clinical; operations by IQVIA; analyses by sponsor and independently confirmed by George Clinical; sponsor-funded editorial assistance (MedErgy); several authors report fees/grants from Janssen and other manufacturers.

2. Research question

Canagliflozin and renal outcomes in type 2 diabetes with nephropathy

3. Study design and population

Study design

Randomised controlled trial – Randomised, double-blind, placebo-controlled, event-driven multicentre RCT (CREDENCE, NCT02065791) with 2-week single-blind placebo run-in; stopped early at the planned interim analysis for efficacy

Population

Adults >=30 years with type 2 diabetes (HbA1c 6.5-12.0%), eGFR 30 to <90 ml/min/1.73 m2 and UACR >300-5000 mg/g on stable maximum-tolerated ACEi/ARB; mean age 63.0 years, 33.9% women, mean HbA1c 8.3%, mean eGFR 56.2, median UACR 927; 50.4% with cardiovascular disease; 5.3% prior amputation

Country

690 sites in 34 countries

Period

Randomisation March 2014 to May 2017; data censored 30 October 2018; median follow-up 2.62 years (range 0.02-4.53)

Sample size

4,401 randomised (2,202 canagliflozin, 2,199 placebo); 12,900 screened

Inclusion and exclusion criteria

Included: T2DM, HbA1c 6.5-12.0% (6.5-10.5% in Germany), eGFR 30-<90, UACR >300-5000 (central lab), stable ACEi/ARB >=4 weeks, >=80% adherence in run-in. Excluded: suspected non-diabetic kidney disease, type 1 diabetes, immunosuppression for kidney disease, prior dialysis/transplant; dual RAS blockade, direct renin inhibitor or MRA not allowed.

4. Methods and endpoints

Exposure / intervention

Canagliflozin 100 mg

Comparator

Placebo on top of standard care

Endpoints

ESKD, doubling creatinine, renal/CV death

Statistical methods

ITT stratified Cox model by screening eGFR category; group-sequential design with one interim analysis (alpha spending; primary tested at two-sided 0.022); hierarchical testing of 7 secondary outcomes (stopped at CV death, P=0.05); sensitivity analyses with imputation and competing risks; subgroups without multiplicity adjustment; NNT at 2.5 years from Kaplan-Meier.

5. Actual results

Results

Primary composite (ESKD, doubling of creatinine, renal or CV death): 245/2202 vs 340/2199; 43.2 vs 61.2 per 1000 patient-years; HR 0.70 (95% CI 0.59-0.82), P=0.00001. ESKD HR 0.68 (0.54-0.86); doubling of creatinine HR 0.60 (0.48-0.76); renal composite HR 0.66 (0.53-0.81); CV death/HF hospitalisation HR 0.69 (0.57-0.83); CV death/MI/stroke HR 0.80 (0.67-0.95); HF hospitalisation HR 0.61 (0.47-0.80); CV death HR 0.78 (0.61-1.00), P=0.05; all-cause death HR 0.83 (0.68-1.02, not formally tested). Safety: amputation 12.3 vs 11.2 per 1000 PY, HR 1.11 (0.79-1.56); fracture HR 0.98 (0.70-1.37); adjudicated diabetic ketoacidosis 11/2200 vs 1/2197 (2.2 vs 0.2 per 1000 PY; HR 10.80, 1.39-83.65); serious AE related to trial drug HR 1.45 (0.98-2.14); any serious AE HR 0.87 (0.79-0.97); breast cancer 8/761 vs 3/731 (HR 2.59, 0.69-9.76); acute pancreatitis 5 vs 2.

Absolute risks

Per 1000 patients treated for 2.5 years: 47 fewer primary outcome events (NNT 22, 95% CI 15-38), 36 fewer renal composite events (NNT 28), 24 fewer ESKD (NNT 43), 22 fewer HF hospitalisations (NNT 46), 25 fewer CV death/MI/stroke (NNT 40). DKA excess about 2 per 1000 patient-years (2.2 vs 0.2).

Authors' conclusion

Lower kidney failure and CV events.

6. Strengths

• Large double-blind RCT with placebo run-in, permuted-block stratified randomisation
• Hard renal endpoints and DKA, fractures, pancreatitis, renal-cell carcinoma adjudicated by blinded independent committees
• 99.1% complete follow-up; vital status for 99.9%
• Pre-specified hierarchical testing and stopping rules; independent confirmation of analyses
• Foot-examination protocol amendment after CANVAS amputation signal

7. Weaknesses

• Stopped early at interim analysis (may overestimate effect size; reduced power for secondary outcomes), as authors acknowledge
• Industry sponsorship and author financial ties
• 27.3% discontinued study drug; 84% adherence
• Excluded eGFR <30, non- or microalbuminuric and non-diabetic kidney disease
• Amputation risk may have been mitigated by protocol amendment (foot exams, treatment interruption), limiting transferability of the amputation result to routine care
• Rare harms (DKA, breast cancer) have wide CIs

8. Risk of bias

Orienting tool

RoB 2

Type of assessment

structured assessment based on the full text by a single reviewer (no formal double review)

Full formal assessment

no

Overall risk of bias

low

Rationale

Unchanged (low). Early stopping for benefit may inflate effect size; industry sponsorship. Single-reviewer structured judgement; a formal RoB 2 needs two independent reviewers.

Full-text review (25 October 2026): Added eligibility, 34 countries/690 sites, stopping rules, all secondary HRs, NNTs at 2.5 years, full safety table: DKA 11 vs 1 (HR 10.80, 1.39-83.65), amputation HR 1.11 (0.79-1.56), drug-related serious AE HR 1.45, foot-exam protocol amendment; sponsor roles. Bias unchanged (low).

9. Assessment of the statistical interpretation

Large, precise relative and absolute renal and cardiovascular benefits. Amputation and fracture HRs are close to 1 but CIs (up to 1.56 and 1.37) do not exclude modest increases. DKA was clearly increased in relative terms (HR 10.8) though rare in absolute terms (~2 per 1000 patient-years).

10. Relevance to the specific claim

Contradicts C-ODD-06 (net harm). For C-ODD-05: limits amputation/fracture signals but confirms an adjudicated DKA signal (HR 10.80). Also directly relevant to C-ODD-02 (SGLT2 inhibitor ketoacidosis).

11. Independent contrary findings

Adverse effects listed in archive studies.

12. Transferability to Germany and Europe

Multinational trial including European sites or directly applicable to EU practice.

13. Overall methodological judgement

High-quality evidence that canagliflozin reduces kidney failure and cardiovascular events in T2DM with albuminuric CKD, with no clear excess of amputation or fracture under foot-surveillance conditions, but with a confirmed, rare excess of diabetic ketoacidosis. Contradicts 'net harmful/kills' claims; partly supports the existence of documented SGLT2-inhibitor harm signals (DKA).

14. Open questions

Amputation risk in routine care without foot-surveillance protocol; DKA risk factors; effects at eGFR <30 and in non-albuminuric CKD.

15. Linked fact checks

• Every major class of glucose-lowering drug (metformin, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 agonists) carries a documented signal of serious harm in the peer-reviewed literature. – Studies with mixed or unclear results
• Glucose-lowering drugs are net harmful and belong among the 'forbidden' items; dapagliflozin (Forxiga) is among the 'dirtiest' drugs and kills the brain; leg amputations happen only to people taking diabetes drugs and insulin. – Studies contradicting or limiting the claim
• SGLT2 inhibitors such as dapagliflozin (Forxiga) can cause ketoacidosis, sometimes with normal or low blood glucose. – Studies supporting the claim